PROJECT SUMMARY ? CORE A Variants in ion channel genes represent the most common genetic finding in severe pediatric epilepsies. However, knowledge of the genetic landscape of channelopathy-associated epilepsy is incomplete, owing to the rapid pace of variant discovery and the challenges of variant interpretation. Further, much of the existing relevant knowledge is not widely available, including recently identified variants, associated clinical phenotypes, protocols for variant functional analysis, and best practices for integrating functional, genetic, and clinical data to assess pathogenicity and prognosis. The Variant Prioritization and Curation Core (Core A) will modify and deploy an existing collaborative bioinformatics and variant curation platform to support the mission of our Center. Core A will serve as an interface to ongoing NIH curation efforts, including ClinVar and ClinGen, to ensure that functional data generated by the Center are enduring and fully accessible. In Aim 1, we will catalog variants in the epilepsy-associated voltage-gated ion channel genes. To maximize the utility of in vitro and in vivo functional studies performed in Projects 1-3, Core A will establish and maintain a database of known epilepsy-associated variants in voltage-gated ion channel genes. We will assemble genetic and phenotypic information from diverse sources including publications, locus-specific databases, previously undisclosed data from diagnostic laboratories (~30,000 patients) and research studies (~20,000 subjects). In Aim 2, we will prioritize variants in ion channel genes for functional evaluation. Ion channel gene variants of the highest clinical importance and analytical validity will be selected for the high-throughput studies proposed in Project 1. To identify which variants meet this standard, we will apply a range of criteria including established American College of Medical Genetics and Genomics (ACMG) diagnostic rules and an advanced data-driven algorithm that considers mutational ?hot spots,? gene family information, and regional intolerance. Based on the applied criteria, we will prioritize 1,000 variants for functional evaluation over the 5-year funding period. In Aim 3, we will use functional data to iteratively refine variant classifications and diagnostic criteria. We will apply results from the Center to propose improved classification rules for variants and work within the ClinGen consortium to develop a gene/variant-based taxonomy of early onset epilepsy that harmonizes with the International League Against Epilepsy (ILAE) classification and terminology. To ensure public access, Core A members will expand their ongoing collaboration with the NIH-funded ClinGen consortium, and the ClinVar archive by submitting all classified ion channel variants and key supporting evidence to ClinVar as an Expert Panel. As part of this effort, we will augment existing ClinVar data elements to include data fields on variant function using an ontology developed by Project 1.